Since the 19th century, human diseases have largely been defined by the organ system in which they are most obviously manifest, and often so at end-stage. The biomedical community now recognizes that many different diseases have common mechanisms and common intermediate pathophenotypes (e.g., inflammation, thrombosis, apoptosis, and fibrosis). Based on this perspective of disease pathogenesis, the site of disease expression may be viewed a consequence of the local environment and of the differential expression of determinants of the intermediate pathophenotype in that environment. We, therefore, propose as a central hypothesis that different complex diseases are governed by common network- associated determinants of common intermediate pathophenotypes, and that what differentiates these complex diseases from one another is the balance among the intermediate pathophenotypes, and the molecular context within which they are expressed. To test this hypothesis, we will focus on three different diseases-acute myocardial infarction, venous thromboembolism, and acute ischemic stroke-and two intermediate pathophenotypes-inflammation and thrombosis-via three interdisciplinary specific aims. First, we will develop network models of pathways that govern inflammation and thrombosis. Concomitantly, we will utilize two large population-based whole genome scans to perform structured genetic analysis to identify components of inflammatory and thrombotic pathways related to the different diseases. By combining this genetic analysis with network models, we will begin to construct subnetwork maps of elements of the 'inflammasome'and 'thrombosome'common to these diseases and elements that distinguish them from one another. Second, using data sets derived from trials of the anti-inflammatory agent, rosuvastatin, and the antithrombotic agent, aspirin, in initially healthy individuals, we will examine the effect of therapeutic perturbation of the inflammasome and thrombosome on the incidence of each disease as determined by gene status. We will also utilize key molecular mediators of the inflammasome and thrombosome common to and distinctive for these three diseases in correlative, iterative mechanism studies using relevant cell systems and animal models. Third, we will integrate the network models of inflammation and thrombosis to develop predictive, probabilistic, multivariate models of manifestations of these diseases. RELEVANCE (See instructions): Taken together, these complementary interdisciplinary approaches focused on three common chronic illnesses should provide information about and potential strategies for redefining these diseases in a mechanistically and molecularly rigorous way. If this approach is successful, it will afford the biomedical community the opportunity to redefine many complex human diseases, leading to potentially novel therapeutic and preventive strategies, and promoting the development of truly personalized (individualized) medicine. (End of Abstract)